Discussion
The prevalence of AD is the highest in the infant age group and the
incidence in infants continued to increase during recent years (12, 78).
Because of this high prevalence and the substantial impact that the
disease has on the QoL of both patients and caregivers, safe and
effective treatment options for infants with AD are needed (2, 4, 42).
Treatment should focus on lifelong management, providing rapid symptom
relief to reduce the significant socioeconomic burden as early as
possible (44). Additionally, restoration of the skin barrier by early
treatment may prevent AD worsening into more severe conditions, its
persistence into later life, and the progression of the atopic march
(13, 24, 38, 79). Despite the well-known rationale to initiate treatment
of AD during infancy, there is still an unmet medical need of
alternative treatment options to TCS, which remain the mainstay of
treatment in infants with AD (14). TCIs are one of these alternative
treatment options, overcoming most limitations of TCS, including poor
adherence due to corticophobia and rebound flares upon discontinuation
(16, 46, 53). Additionally, TCIs are steroid-sparing reducing the risk
of chronic exposure to TCS which may result in skin atrophy and
subsequently increased percutaneous absorption of steroids in the
infant, especially when used in sensitive skin areas (14, 22, 47, 49,
58). All studies, except for one, evaluating safety and efficacy of TCIs
for the infant indication have been conducted with pimecrolimus. Based
on the available evidence, the efficacy of pimecrolimus for the
treatment of infants with AD has never been questioned and was also
found to be comparable to the use of TCS in the 5-year PETITE study
(58). Nevertheless, pimecrolimus is in most countries only approved as
second-line treatment for short-term use in children with AD above the
age of 2 years due to initial concerns about long-term safety. Safety
concerns were the result from preclinical carcinogenicity studies
demonstrating that systemic exposure of animals to immunosuppressant
doses of TCIs resulted in malignancies (17, 80). The preclinical safety
concerns were reinforced by cases of lymphoma and skin cancer in
patients who were treated systemically with calcineurin inhibitors
(cyclosporine and tacrolimus) after whole organ transplantation. These
findings ultimately led to the inclusion of a black-box warning in the
US and the second-line use of TCIs in Europe which was based on a
theoretical rather than a proven risk of malignancy (17, 80). However,
systemic exposure to pimecrolimus upon topical application is
negligible, even in infants who have the greatest body surface
area-to-weight ratio (61-63, 65). Accordingly, epidemiological studies
failed to find a causal relationship between use of pimecrolimus and
malignancies in patients with AD (68-70, 72, 74). However, patients
included these studies often only had short or unknown exposure times to
pimecrolimus without focusing on the pediatric population. Therefore,
the 5-year PETITE study was designed to assess the risk on
immunosuppression in infants using pimecrolimus for a median of 224.5
days (58). Based on the results from the PETITE study, topical
pimecrolimus had no effect on the developing immune system and no
malignancies were reported in infants treated with pimecrolimus (58). To
refute the argument that the follow-up time of the PETITE study was
insufficient to examine the association between pimecrolimus and
malignancies, the PEER was initiated in 2004, albeit not in infants but
in pediatric patients above the age of 2 years (71). The most recent
results from the PEER did not report any cases of malignancies that
could be related to immunosuppression and provided the ultimate evidence
that use of topical pimecrolimus is not associated with an increased
cancer risk ((71) and Meda data on file). Another registry similarly
evaluated the long-term safety of tacrolimus ointment in children with
AD. This registry confirmed that there is currently no evidence
supportive of an increased long-term cancer risk in children with AD who
had been treated with TCIs (81). Due to the extensive amount of studies
that have been conducted to evaluate the safety of pimecrolimus for the
treatment of AD in the pediatric population, data on the long-term use
of pimecrolimus are now surpassing these collected for mid- to
high-potency TCS (82). After nearly 20 years of clinical experience, the
Expert Panel concluded accordingly that it is no longer appropriate to
restrict the use of pimecrolimus to children above the age of 2 years.
This is reflected particularly by the recent approval of pimecrolimus
for treatment of infants with AD and the removal of the black-box
warning in Canada in 2019 (83). Additionally, the recently published
consensus-based European guidelines recommend long-term use of TCIs for
sensitive skin areas in the pediatric population (14). Based on the
available evidence and expert opinion, the European Expert Panel
concludes that treatment of AD should be initiated as early as infancy,
and topical pimecrolimus is a safe and effective steroid-sparing
treatment option for both short and long-term use, that should no longer
be withheld from infants aged 3 months and above.